Administration of avermectin/milbemycin compounds for the treatment of ophthalmic pathologies

ABSTRACT

Administration of at least one compound of the family of the avermectins or of the family of the milbemycins, notably ivermectin, is useful for the treatment of ophthalmic pathologies, including ocular rosacea.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/160,408, filed Jun. 14, 2011, now allowed, which is a continuation ofUS Application No. 12/059,086, filed Mar. 31, 2008, now abandoned, whichis a continuation of PCT/IB2006/003864 filed September 29, 2006 anddesignating the United States, published in the English language as WO2007/054822 A2 on May 18, 2007, which claims benefit under 35 U.S.C.§119(e) of US Provisional Application No. 60/725,320, filed Oct. 12,2005 and of US Provisional Application No. 60/818,316, filed Jul. 5,2006, and which claims foreign priority of FR 0510025, filed Sep. 30,2005, each hereby expressly incorporated by reference in its entiretyand each assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the formulation of at least onecompound of the family of the avermectins or of the family of themilbemycins into pharmaceutical compositions useful for the treatment ofophthalmic pathologies, including ocular rosacea.

2. Description of Background and/or Related and/or Prior Art

Ocular rosacea is frequently diagnosed when it coexists with cutaneoussigns or symptoms of rosacea (Browning D. J. and Proia A. D., OcularRosacea, Surv. Ophthalmol., 1986, 31, 145-58). Ocular rosacea isindependent of the severity of rosacea of the skin (Donshik P. C., FlossD. M. and Ehlers W. H., Inflammatory and papulosquamous disorders of theskin and eye, Dermatologic Clinics, 1992, 3, 533-47).

In the event of ocular attack, certain studies show more women affectedthan men, whereas there is no significant difference according to sexfor rosacea of the skin (Ramelet A. A., Rosacea: a reaction patternassociated with ocular lesions and headache, Arch. Dermatol., 1994, 130,1448).

For a proportion of patients affected by ocular rosacea ranging up to20%, the ocular signs and symptoms can occur before the cutaneousmanifestations. The relevant symptoms for the diagnosis of ocularrosacea are as follows: feeling of burning or of smarting, feeling of aforeign body, feeling of dryness of the eye, increased sensitivity tolight, blurred vision. The least serious clinical signs in patientsaffected by ocular rosacea are telangiectasia of the eyelid margin,meibomitis, chalazia, conjunctival hyperaemia and papillaryconjunctivitis (Donshik P. C., Floss D. M. and Ehlers W. H.,Inflammatory and papulosquamous disorders of the skin and eye,Dermatologic Clinics, 1992, 3, 533-47). Dryness of the eye withquantitative deficiency of tears and bacterial superinfection frequentlyexist.

More serious are the problems posed by attacks on the cornea in the formof superficial punctuate keratitis and interstitial keratitis, which candevelop into a decrease in visual acuity, ulceration or perforation(Jenkins M. S., Brown S. I., Lempert S. L. and Weinberg R. J., OcularRosacea, Am. J. Ophthalmol., 1979, 88, 618-22).

The causes of the ocular pathologies indicated above include, inparticular, the presence of various organisms, such as Demodexfolliculorum, the commonest human ectoparasite. However, not all ocularpathologies are related to the presence of this ectoparasite.

If ocular rosacea, which is included among ophthalmic pathologies, isnot treated, serious complications may occur in the cornea and this candetrimentally affect the vision.

The therapeutic measures commonly employed are the application of hotcompresses and of topical antibiotics, such as a metronidazole gel, forexample. A marked improvement is obtained but is often followed by arelapse in the form of conjunctivitis.

Oral antibiotics, such as tetracycline hydrochloride or doxycycline, canalso be administered. However, the level of relapse is on the order of66% after treatment for 6 months (Zug K. A., Palay D. A. and Rock B.,Dermatologic diagnosis and treatment of itchy red eyelids, Surv.Ophthalmol., 1996, 40, 293-306). A maintenance treatment is oftennecessary, sometimes for several years, indeed even for life. Cyclineshave an anti-inflammatory action but do not have a curative action. Thelonger the treatment, the more there exists a risk of appearance ofresistance (Quaterman M. J., Johnson D. W., Abele D. C., Lesher J. L.,Hull D. S. and Davis L. S., Ocular Rosacea, Arch. Dermatol., 1997, 133,49-54). A loss in the anti-inflammatory effectiveness is possible duringlong-term treatments, hence the interest in short cures (over 1 to 2months). This treatment is used in first application, during severeattacks on the eyes, due to the risk of after-effects on the eyes.

An antibiotic of the class of the macrolides (erythromycin) can also beadministered but the response to the treatment is not systematic.

Furthermore, patients suffering from ocular rosacea must not takeisotretinoin, as this substance aggravates ophthalmic symptoms (MichelJ. L., Valanconny C., Gain P., Montelimard N., Tchaplyguine F. andCambazard F., Manifestations oculaires des rétinoïdes [Ocularmanifestations of retinoids], Ann. Dermatol. Venereol., 1998, 125,438-42).

None of these treatments makes possible complete and lasting remissionof ocular rosacea. In view of the above, there thus exists a need toformulate a composition which shows an improved effectiveness in thetreatment of ocular rosacea and which does not exhibit the side effectsdescribed in the prior art.

Ivermectin is a mixture of two compounds belonging to the class of theavermectins, 5-O-demethyl-22,23-dihydroavermectin A_(1a) and5-O-demethyl-22,23-dihydroavermectin A_(1b). They are also known underthe names of 22,23-dihydroavermectin B_(1a) and 22,23-dihydroavermectinB_(1b). Ivermectin comprises at least 80% of 22,23-dihydroavermectinB_(1a) and less than 20% of 22,23-dihydroavermectin B_(1b). This activeagent forms part of the class of the avermectins, a group of macrocycliclactones produced by the bacterium Streptomyces avermitilis (Reynolds J.E. F. (Ed), (1993) Martindale, The Extra Pharmacopoeia, 29th Edition,Pharmaceutical Press, London).

In the mid-1980s, ivermectin was indicated as a broad-spectrumanti-parasitic medicament for veterinary application (Campbell W. C. etal. (1983), Ivermectin: a potent new anti-parasitic agent, Science, 221,823-828). It is effective against the majority of common intestinalworms (except for the Teniae), the majority of the acarids and a fewlice. It exhibits in particular a high affinity for theglutamate-dependent chloride channels present in the nerve and musclecells of invertebrates. Its attachment to these channels promotes anincrease in the membrane permeability to chloride ions, resulting inhyperpolarization of the nerve or muscle cell. This results inneuromuscular paralysis, which can bring about the death of certainparasites. Ivermectin also interacts with other ligand-dependentchloride channels, such as those involving the GABA (γ-aminobutyricacid) neuromediator.

Ivermectin is more particularly an anthelmintic. It is indicated in manfor the treatment of onchocerciasis due to Onchocerca volvulus, ofgastrointestinal strongyloidiasis (product Stromectol) and of humanscabies (Meinking T. L. et al., N. Engl. J. Med., 1995, Jul., 6, 331(1),26-30, The treatment of scabies with ivermectin) and in the treatment ofmicrofilaraemia diagnosed or suspected in subjects affected by lymphaticfilariasis due to Wuchereria bancrofti.

Moreover, U.S. Pat. No. 6,133,310 describes the administration ofinvermectin topically in the treatment of rosacea of the skin, in theform of a prototype of a lotion composed of a mixture of invermectin andof water, and also indicates the possibility of a prototype of a creamcomposed, for its part, of the mixture of invermectin and of anexcipient, such as propylene glycol or sodium lauryl sulfate, but doesnot describe any pharmaceutical composition as such. These mixtures aresimilar to experimental preparations to be applied to the skin, usefulin the context of first results of a proof of concept. Specifically, thefacts indicated in this patent do not suggest to one skilled in this artanything regarding the feasibility and the effectiveness ofpharmaceutical compositions acceptable industrially for the treatment ofocular rosacea.

SUMMARY OF THE INVENTION

It has now surprisingly been determined that compounds of the family ofthe avermectins or of the family of the milbemycins, and moreparticularly ivermectin, are suitable for the treatment of ophthalmicpathologies of any origin, particularly ophthalmic pathologies due toDemodex folliculorum, and more particularly ocular rosacea.

The term “treatment” means, according to the invention, treatment inman.

The present invention thus features formulation of at least one compoundselected from among the family of the avermectins and the family of themilbemycins into unique pharmaceutical compositions useful for thetreatment of ophthalmic pathologies, particularly ophthalmic pathologiesdue to Demodex folliculorum, and more particularly ocular rosacea,whether regime or regimen.

The term “pharmaceutical composition” means, according to the invention,a stable composition comprising a therapeutically active agent which hasa good cosmetic quality and a satisfactory time limit (18 monthsminimum).

According to the invention, the term “unique pharmaceutical composition”means that the composition comprising the compound(s) of the family ofavermectins and/or of the family of the milbemycins is administeredalone to treat the ophthalmic pathologies; combinations with otherpharmaceutical compositions are thus excluded.

Preferably, according to the present invention, the compound(s) of thefamily of the avermectins and/or of the family of the milbemycins is(are) the only active principle(s) employed in the composition fortreating ophthalmic pathologies; no active principle other than theavermectins and milbemycins, whether in particular administeredtopically or orally, is employed according to the invention.

The term “avermectins” means in particular a compound selected fromamong ivermectin, invermectin, avermectin, abamectin, doramectin,eprinomectin, emamectin and selamectin.

The term “milbemycins” means in particular a compound selected fromamong lepimectin, milbemectin, milbemycin oxime and moxidectin,nemadectin.

The compound selected is preferably ivermectin.

The present invention also features formulation of ivermectin intopharmaceutical compositions useful for the treatment of ophthalmicpathologies, particularly ophthalmic pathologies due to Demodexfolliculorum, and more particularly ocular rosacea.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

The pharmaceutical compositions according to the invention, comprisingat least one compound selected from among the family of the avermectinsand the family of the milbemycins, and preferably ivermectin, areparticularly useful for the treatment of ophthalmic symptoms, symptomsselected from a feeling or sensation of burning or of smarting of theeye, a feeling or sensation of a foreign body in the eye, a feeling orsensation of dryness of the eye, an increased sensitivity to light,blurred vision, telangiectasia of the eyelid margin, meibomitis,chalazia, conjunctival hyperaemia and papillary conjunctivitis.

According to another embodiment of the invention, the pharmaceuticalcomposition comprising at least one compound selected from the family ofthe avermectins and the family of the milbemycins, and preferablyivermectin, is administered in particular for the treatment ofconjunctivitis or blepharitis.

The pharmaceutical compositions according to the invention are usefulfor the treatment of the eyes topically, orally, parenterally orrectally.

The topical application is the most common method of administration ofophthalmic medicaments. The topical route makes possible theinstillation into the eye of drops or the application in the eye ofsolutions, eyewashes, suspensions, salves, ointments, gels, sprays,foams, powders, lotions, viscoelastic solutions and/or the deploying ofsolid forms at the surface of the eye, impregnated pads, syndets orwipes.

Same can also be provided in the form of suspensions of microspheres ornanospheres or of vesicles formed from lipid or polymer or of polymericpatches and of hydrogels making possible controlled release. Thesecompositions for topical application can be provided in anhydrous form,in aqueous form or in the form of an emulsion.

The pharmaceutical compositions for topical application must benon-irritating and compatible with the tissues of the eye. The solutionsare sterile preparations free from all particles. The suspensions aresterile preparations comprising solid particles in a liquid vehicleappropriate for ocular instillation. The ointments are semisolid andsterile preparations.

Orally, the pharmaceutical compositions can be provided in liquid, pastyor solid form, in the form of powders and more particularly in the formof tablets, including sugar-coated tablets, hard gelatin capsules,syrups, suspensions, solutions, powders, granules, emulsions,microspheres or nanospheres or vesicles formed from lipid or polymermaking possible controlled release.

Parenterally, the compositions can be provided in the form of solutionsor suspensions for infusion or for injection.

Rectally, the compositions can be provided in the form of suppositories.

The compositions according to the invention preferably comprise from0.001% to 10% of at least one compound selected from the family of theavermectins and the family of the milbemycins, preferably ivermectin, byweight with respect to the total weight of the composition. Morepreferably, the compositions according to the invention comprise from0.01% to 5% of at least one compound selected from the family of theavermectins and the family of the milbemycins, preferably ivermectin, byweight with respect to the total weight of the composition.

In a preferred alternative embodiment of the invention, the subjectpharmaceutical compositions are for topical application.

More preferably, the compositions according to the invention areprovided in the form of an eyewash or of eye drops. The term “eyewash”means a liquid formulation specifically appropriate for administrationto the conjunctiva of the eye and the cornea. The eyewash ischaracterized by a volume of the instilled drops of approximately 25-50microliters.

As indicated above, the compositions according to the invention have tomeet specific conditions in order to be applied in the eye. Suchconditions include, in particular, sterility, absence of irritation andcompatibility with the tissues of the eye. The latter criterion is moredifficult to obtain than for a composition applied to the skin; inparticular, compounds such as ethanol or glycols, formulated incompositions to be applied to the skin, cannot be included incompositions for ocular use.

The topical compositions according to the invention make it possible todirectly and specifically treat the symptoms of the pathology in the eyeand eyelids by a local action; in particular, since only the eye istargeted, a better effectiveness can be expected.

Furthermore, the topical compositions according to the inventionpreferably being the only ones administered to treat ocular rosacea,interactions from active principles can be reduced, indeed even avoided.

The pharmaceutical compositions according to the invention canadditionally comprise inert additives or combinations of theseadditives, such as:

-   wetting agents, emollients;-   agents for improving flavor;-   preservatives;-   stabilizing agents;-   agents for regulating moisture;-   pH-regulating agents;-   buffers;-   agents for modifying osmotic pressure;-   emulsifying agents;-   agents for increasing viscosity;-   and antioxidants.

Of course, one skilled in this art will take care to choose the optionalcompound or compounds to be added to these compositions such that theadvantageous properties intrinsically associated with the presentinvention are not, or not substantially, detrimentally affected by theenvisaged addition.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

EXAMPLE 1

Ivermectin 0.03% Polysorbate 80 2.00% Benzalkonium chloride 0.05% EDTA0.05% Water q.s. for 100 Buffer system pH 6.3

EXAMPLE 2

Ivermectin 0.10% Polysorbate 80 5.00% Phenylethyl alcohol 0.50%Hydroxypropylcellulose 1.20% Sorbitol 2.00% Water q.s. for 100Monosodium phosphate/sodium q.s. pH 6.5 sulfite heptahydrate (buffersystem)

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A pharmaceutical composition useful for the treatment of symptoms ofocular rosacea in the eye(s), said composition comprising a thuseffective amount of ivermectin, formulated into an eyewash compositionwith a pharmaceutically acceptable vehicle therefor, wherein ivermectinis the sole active ingredient for treating said symptoms of ocularrosacea in said eyewash composition, said eyewash composition beingsterile, non-irritating and compatible with eye tissue, said eyewashcomposition comprising ivermectin, polysorbate 80, benzalkoniumchloride, EDTA, water and a buffer system to adjust pH, said eyewashcomposition comprising from 0.001% to 0.10% by weight of ivermectinrelative to the total weight of the composition. 2-22. (canceled)